Dispenser comprising ionophore

ABSTRACT

A dispenser is disclosed for delivering a beneficial ionophore to an animal. The dispenser comprises (1) a semipermeable housing defining an internal space, (2) at least one composition comprising an ionophore and a pharmaceutically acceptable carrier in the space, (3) an expandable hydrophilic composition in the space, (4) a dense member in the space, and (5) at least one exit passageway in the housing for delivering the ionophore from the dispenser.

This application is a continuation-in-part of application Ser. No.07/381,423, filed on Jul. 18, 1989.

DESCRIPTION OF TECHNICAL FIELD

This invention pertains to the delivery of an ionophore to an animal,and particularly to livestock. More particularly, the invention isconcerned with the controlled administration of an ionophore to ananimal for treating an infectious disease, for improving feedefficiency, and for the enhancement of growth of the animal.

DESCRIPTION OF BACKGROUND OF THE INVENTION

Ionophores, or ion-bearers, as reported in Ann. N.Y. Acad. Scil, Vol.264, pp. 373-86 (1985), are polyether antibiotics that modulate thephysiological transport of ions across biological membranes and alterthe characteristics of fermentation in the animal, resulting infavorable metabolic changes. These valuable properties of ionophores ledto their use as feed additives by the livestock industry. For example,the ionophores, when fed to ruminants, resulted in an improved feed-gainratio, as reported in Feedstuffs, pp. 14, 15 and 22 (1989). In oneaccepted use, ionophores are fed to feedlot cattle in confinement forimproved feed efficiency. In this use, the ionophore first is mixed witha finely ground nonmedicated feedstuff to produce a premix, which premixis added to an air-dry feed for feeding to cattle, including steers andheifers.

While the above described prior art use of ionophore results in improvedfeed efficiency, usually of from 5 to 8 percent or higher, for steersand heifers, as reported in Feedstuffs (supra), serious shortcomingsaccompany this use. For example, since the ionophore is mixed with feed,one shortcoming is the difficulty to ascertain the amount of ionophoreingested by the animal because of feedlot losses such as spillage andscatter. Another shortcoming resides in the absence of controlledadministration of known amounts of the ionophore over time, as thecomposition of the feed charged with the ionophore can vary with feedmillers. Also, ionophores are sensitive to moisture in the environment,which moisture can adversely affect their usefulness, and the handlingand transport of feeds containing ionophores can result in thesegregation of particles carrying ionophores and change theconcentration level to which cattle are exposed when fed over time.Then, since ionophores usually are mixed with feeds daily, this requiresextra labor that adds to the cost of the ionophore-feedstuff.

In the light of the above presentation, it will be appreciated by thoseversed in the dispensing art to which this invention pertains that apressing need exists for a dosage form that can deliver a valuableionophore to a biological environment of use comprising livestock forboth improved feed efficiency and the enhancement of growth of thelivestock. The pressing need exists also for a dosage form that canstore and deliver an ionophore at a controlled rate in a substantiallyconstant dose per unit time over a prolonged period of time essentiallyindependent of the environment of use, which environment of use pertainsto livestock that are confined and to livestock in the pasture. It willbe appreciated further by those versed in the dispensing art that ifsuch a novel and unique dosage form is provided that can administer anionophore in a rate-controlled dose over time and, simultaneously,provide the beneficial effects, the dosage form would represent anadvancement and valuable contribution in the ionophore dosage form art.

SUMMARY OF THE INVENTION

The present invention provides a dispenser or other dosage form fordelivering an ionophore in a rate-controlled manner to an animal over anextended period of time to produce the desired beneficial ionophoreeffects. The dispenser comprises a housing defining an internal space orlumen, at least one composition comprising an ionophore and apharmaceutically acceptable carrier in the space or lumen, an expandablehydrophilic composition in the space or lumen, a densifier in the spaceor lumen, and at least one exit passageway in the housing for deliveringthe ionophore from the dispenser. The dispenser can have a highionophore loading and is self-contained, self-starting and self-poweredin a fluid environment of use. The invention also provides a compositionof matter comprising an ionophore and a pharmaceutically acceptablecarrier for administration to animals.

With the dispenser and the composition of this invention, the ionophoremay be dispensed to livestock in the pasture as well as to livestock inconfinement. The ionophore may be administered in a different, oftenlower, overall dosage than the dose required if mixed with foodstuffs,and the amount of ionophore administered is exactly known and can becontrolled.

BRIEF DISCLOSURE OF THE DRAWINGS

In the drawing figures, which are not drawn to scale but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

FIG. 1 is a view of a dosage form designed and manufactured as adispenser for administering a beneficial ionophore to a warm-bloodedanimal;

FIG. 2 is a view of another dosage form provided by the invention sizedand adapted for administering a beneficial ionophore to a warm-bloodedanimal over a prolonged period of time;

FIG. 3 is an opened view of the dosage form of FIG. 1 through 3--3thereof for illustrating the structure of the dosage form in oneembodiment;

FIG. 4 is an opened view of the dosage form of FIG. 2 through 5--5thereof for illustrating a different structural embodiment of the dosageform;

FIG. 5 is an opened view of the dosage form of FIG. 1, wherein thedosage form depicted in FIG. 5 comprises a different internalarrangement and exit means for delivering an ionophore from the dosageform;

FIG. 6 is an opened view of the dosage form of FIG. 1, wherein thedosage form in FIG. 6 illustrates another embodiment of the internalmembers and the exit means;

FIG. 7 is an opened view of a dosage form of the invention, illustratinga different structural embodiment and a different internal arrangementof the dosage form; and

FIGS. 8 through 12 depict release rate patterns for dispensers providedby the invention.

In the drawing figures and in the specification, like parts in relatedfigures are identified by like reference numerals. The terms appearingearlier in the specification and in the description of the drawingfigures, as well as embodiments thereof, are further detailed elsewherein the disclosure.

DETAILED DISCLOSURE OF THE INVENTION DRAWINGS

Turning now to the drawings in detail, which drawings are examples ofvarious dosage forms provided by the invention and which examples arenot to be construed as limiting, one example of a dosage form is seen inFIG. 1. In FIG. 1, a dosage form 10 is seen comprising a body member 11comprising a wall 12 that surrounds an internal lumen not seen inFIG. 1. Dosage form 10 comprises a lead end 9 and a rear end 8. Lead end9 comprises a wide exit passageway 13 for releasing a beneficialionophore form dosage form 10 to a biological environment of use.

FIG. 2 illustrates another embodiment of dosage form 10 provided by thisinvention. In FIG. 2, dosage form 10 comprises lead end 9, rear end 8,body 11 and wall 12. Lead end 9 comprises more than one, or amultiplicity of exit passageways 13 through wall 12 for releasing abeneficial ionophore from dosage form 10.

In FIG. 3, dosage form 10 of FIG. 1 is seen in opened section through3--3 of FIG. 1. In FIG. 3, dosage form 10 comprises lead end 9, rear end8, a body 11, and a wall 12 that surrounds and forms an internal lumenor compartment 14 that communicates through a wide exit passageway 13with the exterior of dosage form 10. Wall 12 of dosage form 10 comprisestotally a semipermeable composition, or wall 12 comprises at least inpart a semipermeable composition. The remainder of wall 12, in thelatter embodiment, may comprise a composition that is substantiallynonpermeable to the passage of an exterior fluid present in theenvironment of use. Both semipermeable and nonpermeable portions of wall12 are substantially impermeable to the passage of ingredients presentinside dosage from 10, are non-toxic and maintain physical and chemicalintegrity during the delivery of the beneficial ionophore from dosageform 10.

Internal compartment or lumen 14 comprises a first composition 15 and asecond composition 16. The first composition 15 comprises a beneficialionophore represented by dots 17, and the second composition 16comprises a beneficial ionophore represented by dots 18. The first andsecond compositions comprise at least one or more than one ionophore.The first and second compositions comprise like or unlike ionophores.The first and second compositions comprise the same dosage unit amountsor the compositions comprise different dosage unit amounts of anionophore. First composition 15 also comprises a pharmaceuticallyacceptable carrier, represented by slanted lines 19, for ionophore 17;and the second composition 16 also comprises a pharmaceuticallyacceptable carrier, represented by slanted lines 20, for ionophore 18.Carriers 19 and 20 can be the same or different in compositions 15 and16. In both embodiments carriers 19 and 20 imbibe and/or absorb andexternal fluid that enters compartment 14 and form thereby a dispensablecomposition for transporting ionophores 17 and 18 from dosage form 10.First composition 15 and second composition 16 in a preferred optionalembodiment comprise a composition-forming member such as a binder, atableting agent or a lubricant represented in composition 15 by wavyline 21 and in composition 16 by wavy line 22. Composition-formingmembers 21 and 22 can be the same or they can be different incompositions 15 and 16.

Dosage form 10 in compartment 14 further comprises an expandable drivingmember 23 that is in contact with second composition 16. Expandabledriving member 23 has a shape that corresponds to the internal shape ofcompartment 14. Expandable driving member 23, in the presence of anexternal fluid that enters compartment 14, imbibes and/or absorbs thefluid, increases in size, and thereby pushes against composition 16 todisplace first composition 15 and second composition 16 from dosage form10. Compartment 14 also comprises a dense member or densifier 24 that isin contact with expandable member 23. Dense member 24 is an importantcomponent of dosage form 10 for keeping dosage form 10 in the rumen ofan animal over a prolonged period of time.

FIG. 4 depicts another manufacture provided by the invention. In FIG. 4,dosage form 10 comprises a body 11 and a wall 12 that surrounds anddefines an internal compartment or lumen 14. Wall 12 comprises in apresently preferred embodiment a semipermeable composition that issubstantially permeable to the passage of an external fluid and issubstantially impermeable to the passage of ingredients contained indosage form 10. Wall 12 is non-toxic and it keeps its physical andchemical integrity; that is, wall 12 does not erode during thedispensing period. Dosage form 10 also comprises a single composition15. Composition 15 comprises at least one ionophore 17 homogeneously orheterogeneously dispensed in a pharmaceutically acceptable carrier 19.Carrier 19 is substantially dry during storage of dosage form 10, andwhen dosage form 10 is in operation in a fluid environment of use andcarrier 19 is in contact with the fluid, carrier 19 changes from arested state to a dispensable state form for delivering ionophore 17from dosage form 10. Dosage form 10 also comprises a dense member 24positioned next to a wide-mouth exit passageway 13 in wall 12. Densemember 24 has a shape that corresponds to the shape of lead end 9 and tothe inside shape of dosage form 10. A passageway 25 extends throughdense member 24 for delivering beneficial composition 15 comprisingionophore 17 through dense member 24 and then through exit passageway 13from dosage form 10. Compartment 14 also comprises an expandable memberdistant from exit passageway 13 at rear end 8. Expandable member 23 isin contact with composition 15 for displacing composition 15 throughpassageways 25 and 13 from dosage form 10. Composition 15 optionallycomprises a composition-forming member 21 such as a binder, a tabletingaid or a lubricant for enhancing the manufacture and the displacement ofcomposition 15 from dosage form 10.

FIG. 5 depicts, in opened view, another manufacture provided by theinvention. In FIG. 5, dosage form 10 comprises a body 11 and a wall 12that surrounds and forms internal lumen or compartment 14. Internalcompartment 14 comprises composition 15, which composition 15 comprisesa pharmaceutically acceptable carrier 19 containing ionophore 17.Compartment 14 also comprises expandable member 23, which member 23optionally comprises an osmotically effective solute 25. A densifier 24is present in dosage form 10 positioned distant from lead end 9. Dosageform 10 comprises a multiplicity of exit passageways 13 in wall 12 atlead end 9. Exit passageways 13 comprise a number of multiplicity ofsmaller openings, generally in a shower-head or screen-like arrangement.The arrangement breaks up composition 15 as composition 15 emergesthrough the exit passageways 13.

FIG. 6 illustrates another embodiment of dosage form 10 provided by theinvention. In FIG. 6, dosage form 10 is seen in opened section and itcomprises rear end 8, leading end 9, body 11, wall 12, lumen orcompartment 14, first composition 15, second composition 16, ionophore17, ionophore 18, nontoxic carrier 19, nontoxic carrier 20,composition-forming member 21, composition-forming member 22, expandablemember 23, densifier 24, and osmotically effective solute 25. Dosageform 10 comprises a multiplicity of exit openings or passageways 13 thatare essentially means for breaking up composition 15 and composition 16as the compositions are pushed at a controlled rate through the exitopenings 13 in wall 12. Exit passageways 13 also function to prevent apremature ejection of a composition from dosage form 10.

FIG. 7 illustrates another embodiment of dosage form 10 provided by theinvention. In FIG. 7, dosage form 10 is seen in opened section and itcomprises rear end 8, flattened leading end 9, body 11, wall 12, lumenor compartment 14, expandable member 23, densifier 24, and osmoticallyeffective solute 25. In FIG. 7, compartment 14 comprises three ionophorecompositions: first composition 15, second composition 16 and thirdcomposition 26. First composition 15 includes ionophore 17, nontoxiccarrier 19 and composition-forming member 21. Second composition 16includes ionophore 18, nontoxic carrier 20 and composition-formingmember 22. Third composition 26 includes ionophore 27, nontoxic carrier28 and composition-forming member 29. The three compositions may allcomprise the same ionophore or they may comprise different ionophores,the ionophores being present in the same or in differing dosage unitamounts. Dosage form 10 also comprises a multiplicity of exitpassageways 13 in wall 12.

The dosage form of the invention can be sized and shaped for deliveringan ionophore to a variety of animals. For example, the dosage form canbe adapted for delivering an ionophore to ruminant animals includingcattle, sheep, giraffes, deer, goats, bison and camels, and moreparticularly cattle and sheep, that comprise an important group ofanimals that require periodic administration of an ionophore. Dosageform 10 can embrace a capsule-like shape and in one design have adiameter of from about 0.5 inches to about 1 inch (about 1.3 cm to about2.5 cm) and a length of from about 0.5 inches to about 2.5 inches (about1.3 cm to about 6.6 cm). For use with cattle, dosage form 10 has adiameter of from about 0.5 inches to about 1.5 inches (about 1.3 cm toabout 3.8 cm), and a length of from about 1 inch to about 4 inches(about 2.5 cm to about 10.2 cm).

While FIGS. 1 through 7 illustrate various dosage forms that can be madeaccording to the invention, it is to be understood that these dosageforms are not to be construed as limiting the invention, as the dosageform can take other shapes, sizes and forms for delivering a beneficialionophore to the biological environment of use. Additionally, while one,two or three ionophore composition layers are illustrated as presentlypreferred embodiments, more than three ionophore layers may be presentwithout departing from the invention.

The dosage form of the invention can be used in veterinary clinics,farms, zoos, laboratories, on the range, in feed lots, and in otherenvironments of use.

MODES OF PROVIDING THE INVENTION

In accordance with the practice of this invention, it has now been foundthat wall 12 can be made with a wall-forming composition that does notadversely affect the animal and does not adversely affect the beneficialionophore and other ingredients in dosage form 10. Wall 12 in at leastpart is semipermeable, that is, the wall is permeable to the passage ofan external fluid such as water and biological fluids and issubstantially impermeable to the passage of ionophore. In a preferredembodiment, all of wall 12 is semipermeable.

Typical materials used for forming wall 12 are, in one embodiment,cellulose esters, cellulose ethers, and cellulose esterethers. Thecellulose polymers have a degree of substitution D.S., on their anhydroglucose unit of from greater than 0 up to 3, inclusive. By "degreeof substitution" is meant that the average number of hydroxyl groupsoriginally present on the anhydroglucose unit comprising the cellulosepolymer that are replaced by a substituting group. Representativematerials include a member selected from the group consisting of acellulose acylate, cellulose diacylate, cellulose triacylate; celluloseacetate, cellulose diacetate, cellulose triacetate; mono-, di-, andtricellulose alkanylates; mono-, di-, and tricellulose aroylates; andthe like. Exemplary polymers include cellulsoe acetate having a D.S. upto 1 and an acetyl content up to 21%; cellulose acetate having a D.S. of1.8 to 2.3 and an acetyl content of 32% to 39%; cellulose diacetatehaving a D.S. of 1 to 2 and an acetyl content of 21% to 35%; cellulosetriacetate having a D.S. of 2 to 3 and an acetyl content of 34% to44.8%; and the like. More specific cellulose polymers include cellulosepropionate having a D.S. of 1.8, a propyl content of 39.2% to 45% and ahydroxyl content of 2.8% to 5.4%; cellulose acetate butyrate having aD.S. of 1.8, an acetyl content of 13% to 15% and a butyrl content of 34%to 39%; cellulose acetate butyrate having an acetyl content of 2% to29%, a butyryl content of 17% to 53% and a hydroxyl content of 0.5% to4.7%; cellulose triacylate having a D.S. of 2.9 to 3 such as cellulosetrivalerate, cellulose trilaurate, cellulose tripalmitate, cellulosetrisuccinate and cellulose trioctanoate; cellulose diacylate having aD.S. of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate,cellulose dioctanoate and cellulose dipentanoate; coesters of cellulosesuch as cellulose acetate butyrate and cellulose acetate propionate; andthe like.

Additional polymers include ethyl cellulose of various degrees ofetherification with ethoxy content of from 40% to 55%; cellulose acetateethyl carbamate; cellulose acetate methyl carbamate cellulose acetatediethyl aminoacetate; semipermeable polyurethanes; semipermeablesulfonate polystyrenes; semipermeable cross-linked polymers formed bythe coprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876, 3,276,586, 3,541,005, 3,541,006, 3,546,142,4,595,583 and 4,783,337; and the like. Semipermeable polymers also aredisclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132.Semipermeable lightly cross-linked polymers, semipermeable cross-linkedpoly(sodium styrene sulfonate), semipermeable cross-linkedpoly(vinylbenzyltrimethyl) ammonium chloride, semipermeable polymersexhibiting a fluid permeability of 2.5×10⁻⁸ to 2.5×10⁻⁴ (cm² /hr.atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross a semipermeable membrane are disclosed in U.S. Pat. Nos.3,845,770, 3,916,899 and 4,160,020; and in "Handbook of Common Polymers"by Scott, J. R. and Roff W. J. (1971), published by CRC Press,Cleveland, Oh.

Semipermeable wall 12 also can comprise a flux-regulating agent. Theflux-regulating agent is a compound that assists in regulating thepermeability of a fluid through the semipermeable wall. Flux-regulatingagents that increase the permeability of a wall to fluid, such as water,are essentially hydrophilic. The amount of regulator in the wall, whenincorporated therein, generally is from about 0.01 weight percent (wt %)to 35 wt % or more. The flux-regulator agents in one embodiment comprisea member selected from the group consisting of a polyhydric alcohol,polyalkylene glycol, polyalkylenediol, polyester of alkylene glycol, andthe like. Typical flux enhancers comprise polyethylene glycol 300, 400,600, 1500, 4000, 6000, and the like; low molecular weight glycols suchas polypropylene glycol, polybutylene glycol, and polyamylene glycol;the polyalkylenediols such as poly(1,3-propanediol),poly(1,4-butanediol), poly(1,6-hexanediol), and the like; aliphaticdiols such as 1,3-butylene glycol, 1,4-pentamethylene glycol,1,4-hexamethylene glycol, and the like; alkylene triols such asglycerine; 1,2,3-butanetriol, 1,2,4-hexanetriol, 1,3,6-hexanetriol, andthe like; esters such as ethylene glycol dipropionate, ethylene glycolbutyrate, butylene glycol dipropionate, and the like.

Semipermeable wall 12 optionally comprises a plasticizer, for impartingflexibility and elongation properties to the wall, for making the wallless to nonbrittle, and for enhancing the manufacturing properties ofthe wall. Plasticizers useful for the present purpose comprise dihexylphthalate, butyl octyl phthalate, triacetin, dioctyl azelate, epoxidizedtallate, sucrose acetate isobutyrate, epoxidized soybean oil, citricacid esters, phosphate esters, tricresyl phosphate, triacetyl phosphate,adipate esters, sebacate esters, and other nontoxic plasticizers. Theamount of plasticizer in wall 12, when incorporated therein, is about0.01 wt % to 40 wt % or more.

Beneficial ionophores that can be dispensed using the dosage form ofthis invention comprise natural and synthetic ionophores. The ionophoresare polyethers and they possess the ability to transport mono- anddivalent cations across lipid bilayers which lie within biologicalmembranes. The ionophores possess unique properties which derive fromtheir ability to perturb transmembrane ion gradients and electricalpotentials. The ability of ionophores to complex and transport ionsleads to their applications as antibiotics against gram-positivemicroorganisms, against mycobacteria, as growth promotants in ruminantssuch as cattle and sheep, and for improved feed utilization as seen byincreasing the efficiency of meat production. Ionophores that can bestored and dispensed by the dosage form of this invention comprise amember selected from the group consisting of azolomycin, valinomycin,enjactin, monactin, nonactin, dinactin, trinactin, virginiamycin,tetronasin, semduramicin, monensin, monensin sodium, monensin factor B,monensin factor C, nigericin, narasin also known as methyl salinomycin,salinomycin, isolasalocid, lasalocid, lysocellin, septamycin,laidlomycin, laidlomycin propionate, laidlomycin butyrate, lonomycin,lenotemycin, grisorixin, ferensimycin, alborixin, rosgramicin,erythromycin, sodium lysocellin, and the like. The polyethers includebambermycin, monenomycin, flavomycin, and the like. The ionophores alsocomprise the pharmaceutically acceptable derivative having ionophoreactivities, such as the pharmaceutically acceptable salts, the alkyl andalkenyl derivatives, the monoglycoside and diglycoside derivatives, thehydroxylated derivatives, the free acid, the hydrate, the esterderivatives, the ether derivatives, and the like. In one presentlypreferred embodiment, the ionophores exhibit a molecular weight of about350 to 2500.

The ionophore is present in the invention in a therapeutically effectiveamount; that is, in an amount that is necessary to provide a desiredtherapeutic, usually beneficial, effect. The presently preferred amountof an ionophore in a dosage form, present in a single composition, infirst and second compositions, or in first, second and thirdcompositions, generally is from about 10 milligrams to 100 grams,preferably from about 10 milligrams to 30 grams. The amount of ionophorein a first and a second composition or in a first, a second and a thirdcomposition can be the same or different, with the total amount ofionophore in all compositions in the dispenser equal to a maximum of 100g, and preferably to a maximum of 30 g. The first, second and/or thirdcompositions can comprise one or more than one like or unlikeionophores. The dosage form provided by the invention can delivervarious dosage amounts of an ionophore, for example, from 10 mg per dayto 500 mg per day, for 150 days or longer. The ionophores are known inthe ionophore art in "Kirk-Othmer Encyclopedia", Vol., 3, pp. 47-64(1978); Ann. N.Y. Acad. Sci., Vol, 264, pp. 373-86 (1975); and ACS Sym.,Ser. 140, pp. 1-22 (1980). The ionophore can be present as a base, as asalt, as an ester, or as another derivative thereof.

The pharmaceutically acceptable carriers 19, 20 and 28 forming thefirst, second and third compositions 15, 16 and 26 and comprisingionophores 17, 18 and 27 comprise pharmaceutically acceptable polymersthat are hydrophilic, nontoxic, and substantially free of reaction withan ionophore and other members forming dosage form 10. Thepharmaceutically acceptable carrier comprising an ionophore providesunexpected advantage such as (a) the ability to store a high dosageamount, up to 95 wt %, of an ionophore; (b) the ability to dispense anionophore in controlled, small doses over a prolonged time up to about 5or 6 months or longer; (c) the ability to substantially protect a fluidsensitive ionophore from fluid that enters the dosage form, by harboringthe ionophore within its polymeric structure; and (d) the ability tocharge high loadings of an ionophore in a polymer carrier that undergoeschange from a rested state to a dispensable state possessing adispensable viscosity, or to a semisolid dispensable state duringoperation of the dosage form. The polymer carriers useful for thepresent purpose comprise a member selected from the group includingpolyethylene oxide polymers having a 1,000,000 to 7,500,000 molecularweight; carboxy vinyl polymers, sometimes referred to ascarboxymethylene, commercially available as Carbopol® polymer possessinga 200,000 to 5,000,000 molecular weight; poly(vinyl pyrrolidone) havinga 125,000 to 460,000 molecular weight; poly(hydroxyalkyl methacrylate)having a 100,000 to 5,000,000 molecular weight; polysaccharides such asagar, karaya, tragacanth, algin, guar, nanthan, and the like, having a50,000 to 2,000,000 molecular weight; and the like.

Expandable layer 23, useful for displacing the first composition, thesecond composition and/or the third composition from the dosage form,comprises a hydrogel composition. The hydrogel composition isnoncross-linked or optionally lightly cross-linked and it possessesosmotic properties such as the ability to imbibe an exterior fluidthrough the semipermeable wall and exhibit an osmotic pressure gradientacross the semipermeable wall. The polymer exhibits the ability toretain a significant fraction of the imbibed fluid in the polymerstructure. The polymers in a preferred embodiment are gel polymers thatcan swell or expand to a very high degree, usually exhibiting a 2- to50-fold volume increase, thereby pushing and displacing the compositioncomprising the ionophore from the dosage form. The swellable,hydrophilic polymers also are known as osmopolymers. The polymers can beof plant, animal or synthetic origin. Polymeric materials useful forforming the expandable layer comprise anionic and cationic hydrogels;polyelectrolyte complexes; a mixture of agar and carboxymethylcellulose;a composition comprising methylcellulose mixed with sparinglycross-linked agar; a water-swellable polymer of N-vinyl lactams;polyethylene oxide possessing a 1,000,000 to 10,000,000 molecularweight; starch graft polymers; sodium carboxymethylcellulose having a90,000 to 1,000,000 molecular weight; a composition comprising sodiumcarboxymethylcellulose and a member selected from the group consistingof hydroxypropylcellulose and hydroxypropylmethylcellulose; and thelike. Representative polymers possessing hydrophilic properties areknown in U.S. Pat. Nos. 3,865,108, 4,002,173, 4,207,893 and 4,327,725,and in Handbook of Common Polymers by Scott and Roff, published by theCleveland Rubber Company, Cleveland, Oh.

Expandable polymer layer 23 optionally comprises an osmoticallyeffective compound 25. Osmotically effective compounds also are known asosmotically effective solutes and as osmagents. The osmoticallyeffective compounds exhibit and osmotic pressure gradient acrosssemipermeable wall 12, and they imbibe fluid into compartment 14. Thepresence of this imbibed fluid provides added fluid for the expandablepolymer to absorb and increase its volume, and the imbibed fluidcontinuously fills the driving area of the compartment and forms a pushmember that urges the first composition, the second composition and/orthe third composition from dosage form 10. Osmotically effectivecompounds or solutes useful for the present purpose comprise magnesiumsulfate, magnesium chloride, sodium chloride, potassium chloride,lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea,sorbitol, inositol, sucrose, glucose, a mixture of sodium chloride andmagnesium chloride, a mixture of potassium chloride and sucrose, and thelike. The osmotic pressure in atmospheres, atm, of osmotically effectivecompounds suitable for the invention will be greater than zero atm,generally from eight atm up to 500 atm, or higher. The amount ofosmotically effective compound blended homogeneously or heterogeneouslywith the swellable polymer is from about 0.02 wt % to 50 wt %.Osmotically effective solutes are known in U.S. Pat. Nos. 4,595,583 andin 4,783,337.

Composition-forming members or tableting aids 21, 22 and 29 optionallyused to provide compositions 15, 16 and 26 may comprise, for example,binders that impart cohesive qualities to the composition such aspoly(vinyl pyrrolidone), natural and synthetic gums such as sodiumalginate, methylcellulose, hydroxypropylmethylcellulose, Veegum®, waxes,and the like; to prevent adhesion to dies and punches during tabletingprocesses, such as a magnesium stearate, calcium stearate, stearic acid,talc, lycopodium, and the like; coloring agents for esthetic qualitiesand identification such as FD&C Blue No. 1; surfactants that aid indispensing the ionophore after its release from the dosage form, such asanionic, cationic, nonionic and amphoteric surfactants; and the like.Composition-forming members are disclosed in Pharmaceutical Sciences,Remington, 14th Ed. (1970). The amount of composition-forming memberpresent in the composition is from about 0.01 wt % to 20 wt %.

The dense member 24, also referred to as density member or densifier 24,is used in delivery system 10 to retain the dosage form in therumen-reticular sac of a ruminant. Dense member 24 allows dosage form 10to remain in the rumen over a prolonged period of time, rather thanletting it pass into the alimentary tract and be eliminated therefrom.As dosage form 10 remains in the rumen, beneficial ionophore isdelivered at a controlled rate to the ruminant over a prolonged periodup to 6 months or longer. Generally, dense member 24 will have a densityof from about 1.0 to 8, or higher, with the density in a presentlypreferred embodiment exhibiting a specific gravity of from 1.5 to 7.6.For the ruminants cattle and sheep, it is presently preferred that densemember 24 exhibit a density to assure complete system density of 2 to 3or greater. Materials that have a density that can be used for formingdense member 24 include iron, iron oxide, iron shot, iron shot coatedwith iron oxide, iron shot magnesium alloy, steel, stainless steel,copper oxide, a mixture of copper oxide and iron powder, and the like.Density of the device may also be achieved by incorporation of bariumsulfate. Dense member 24 in dosage form 10 can embrace differentembodiments. For example, dense member 24 can be machined or cast as asingle, solid piece made of stainless steel having a density of 7.6. Thesolid member is made having a shape that corresponds to the internalshape of system 10. Dense member 24 in another manufacture can be asolid member having an axially aligned bore that extends through thelength of the member. In another embodiment, dense member 20 cancomprise a plurality of dense pellets.

The expression "exit passageway 13", as used herein, denotes an openingor a means in wall 12 suitable for releasing the composition comprisingthe ionophore from dosage form 10. The invention provides a passagewayfor releasing a composition intact and it also provides a passagewaymeans, such as a multiplicity of passageways, for dividing the originalcomposition into smaller compositions as it is released from dosage form10. The release of a composition from dosage form 10, in eitherinstance, embodies a combination of osmotic hydrodynamic pumping anddiffusion properties through an exit passageway or through a series ofexit passageways functioning as an exit port. The dosage form providedby this invention maximizes the release by osmotic pumping and minimizesthe release by diffusion, thereby substantially avoiding mechanicalagitation-dependent drug release. The release rate pattern from a drugdosage form, for example, designed to deliver 85 mg/day of the druglysocellin is as follows in Equation (1): ##EQU1## wherein: ##EQU2##

Then, assuming that negligible water migrates into the drug compositionthrough the wall, Equation (2) follows: ##EQU3## wherein V is therelease rate from the dosage form at 40° C. in cc/day;

ρ_(d) is the drug+pharmaceutical carrier density in mg/cc;

L is the percent drug loading;

k is the water permeability of the wall at 40° C. in ##EQU4## h is thewall thickness in mil (or in mm); Ap is the surface of thepush-composition in contact with the wall; the bottom and top surfacesof the push composition are in contact with the density element and thedrug composition respectively; and,

Δπ is the water imbibition pressure atm.

During operation of the dosage form, Ap×Δπ remains constant; and theiroperation can be illustrated by the accompanying graph wherein Ap×Δπ=C;and ##STR1## wherein, any decrease in osmotic activity is compensatedfor by an increase in the area of the push composition in contact withthe wall. Therefore, it follows according to Equations (3) and (4):##EQU5##

The amount of drug delivered due to diffusion into an environment of useinitially free of drug is set forth by Equation 5: ##EQU6## wherein:##EQU7## D is the diffusion coefficient of the formulated drug inrumenal fluid in cm² /day;

Sep is the surface area of the exit port in cm² ;

h is the thicknesses of the diffusion layer in cm;

Cs is the solubility of formulated drug in rumenal fluid in mg/ml;

L is the percent drug present in the formulation; and

D/h=K is the dissolution rate constant in cm/day.

The composition the ionophore is intermittently eroded at the exitpassageway in the rumen, and the thickness of the diffusion layer variesfrom zero to several mm in thickness. The diffusion layer at the dosageform environment of use interface is very thin and will having minimaleffect on the amount of formulated drug diffusing through the exitpassageway into the rumenal fluid. The two major factors whichcontribute to the diffusion through the exit passageway are:

(1) Surface area of the exit port (Sep); and,

(2) Solubility of the pharmaceutical carrier and the lysocellinionophore in rumenal fluid (Cs).

Following the above presentation, the osmotic release rate for thedosage form comprising a lysocellin ionophore composition can becalculated to be 67 mg/day. The total release rate (dm/dt)_(t) for thelysocellin is 85 mg/day. The diffusional release rate for lysocellin istherefore 18 mg/day.

The effect of the exit passageway diameter increase on the lysocellinrelease rate was calculated to give the following values (for the 85%drug loading):

    ______________________________________                                                                   Exit    Sap exit                                                              passageway                                                                            passageway                                 (dm/dt).sub.t                                                                         (dm/dt).sub.o                                                                          (dm/dt).sub.d                                                                           diameter                                                                              surface area                               mg/day  mg/day   mg/day    mils    cm.sup.2                                   ______________________________________                                        68.7    66.7     2.04      100     0.051                                      74.8    66.7     8.13      200     0.203                                      85.0    66.7     18.31     300     0.456                                      85.0    66.7     18.31     100 × 9*                                                                        0.456                                      99.2    66.7     32.52     400     0.810                                      ______________________________________                                         *9 passageways of 100 mils each                                          

The diffusional release increases with an increase in the exit diameter.For the 300 mil exit diameter, the diffusional release is 21.5%, but fora 400 ml ext, the diffusional release is 33% of the total lysocellinrelease rate.

FIG. 8 shows the effects of the exit passageway diameter on thediffusional release of lysocellin. In FIG. 8, one mil equals 0.0254 mm.

FIG. 9 shows the effects of the exit passageway diameter on the totalrelease of lysocellin from the dosage form.

FIG. 10 depicts the functionality of the dosage form. The release rate(dm/dt)_(t) from the dosage form is about 85 mg/day in vivo. In FIG. 10,the in vivo testing in the rumen of a cow is indicated by squares, thein vitro testing in buffer at pH 8 is indicated by diamonds, and the invitro testing in artificial rumenal fluid is indicated by triangles. Thebuffer is a pH 8 buffer consisting of 140.70 g of potassium phosphateand 38.64 g of sodium hydroxide dissolved in 20 liters of distilledwater. The artificial rumen fluid consists of 124.69 g of sodiumacetate, 53.99 g of sodium propionate, 21.00 g of sodium bicarbonate,81.02 g of sodium succinate, and 29.92 g of butyric acid dissolved in 20liters of distilled water, then bubbled with carbon dioxide for 10minutes.

FIG. 11 shows the results of the effect of the exit diameter increase onthe lysocellin release rate. In FIG. 11, the horizontal line connectedby dashes indicates a constant release rate of 80 mg/day. The line withsquares depicts the release rate through a 400 ml passageway for acomposition comprising lysocellin and a hydrophilic polymer having a7,500,000 molecular weight; the line with triangles pointed up depictsthe release rate through a 300 ml passageway by a composition comprisinglysocellin and a hydrophilic polymer having a 7,500,000 molecularweight; the line with the triangles pointed down depicts the releaserate through a 300 mil passageway for a composition comprisinglysocellin and a hydrophilic polymer having a 5,000,000 molecularweight; and, the line with squares depicts the release rate through a200 mil orifice for a composition comprising a 200 ml passageway and ahydrophilic polymer having a 5,000,000 molecular weight.

The table presented immediately below sets forth the results obtained bycomparing the calculated values with the experimental values obtainedfor a 79% lysocellin loading in a drug composition.

    ______________________________________                                        Drug Carrier                                                                             Calculated  Experimental                                                                             Exit Port                                   Hydrophilic                                                                              (dm/dt).sub.t                                                                             (dm/dt).sub.t                                                                            Diameter                                    Polymer    mg/day      mg/day     mils                                        ______________________________________                                        5,000,000  79          77         300                                         Molecular  69          *60        200                                         Weight                                                                        7,500,000  92          90         400                                         Molecular  79          *66        300                                         Weight                                                                        ______________________________________                                    

The data with an asterisk indicates the experimental value was preparedas follows. The dosage form was designed with one drug composition,comprising 79% or 6 g of lysocellin, and one expandable composition andone composition comprising calcium carbonate. The composition comprisingcalcium carbonate was used as a filler layer to conserve ionophore. Theexpandable composition was placed between the ionophore composition andthe calcium carbonate composition. The ionophore composition faced theexit port and the calcium carbonate composition faced the densityelement. Within about three weeks after the experiment began, theexpandable composition began to occupy space between the wall and thecalcium carbonate composition, thereby diverting some of the push energyaway from the exit port and resulting in the indicated values.

DESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be construed as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomemore apparent to those skilled in the dispensing art in light of thepresent disclosure, the drawings and the accompanying claims.

EXAMPLE 1

A dosage form manufactured in the shape of a dispenser for thecontrolled delivery of lysocellin is made as follows. First, 85 g oflysocellin is passed through a 40 mesh screen. Then, 14.75 g ofpolyethylene oxide having a 5,000,000 molecular weight is passed througha 40 mesh screen. The just-prepared lysocellin and polyethylene oxideare mixed together thoroughly with 0.75 g ofhydroxypropylmethylcellulose having a 11,000 molecular weight to providea homogeneous mix. Then, 30 ml of denatured, anhydrous ethanol is slowlyadded to the blending mixture, and all the ingredients are mixed for anadditional 2 to 3 minutes. The freshly prepared wet granulation ispassed through a 20 mesh screen, allowed to dry at room temperature for16 hours, and again passed through a 20 mesh screen to provide a drugcomposition.

The drug composition is divided into two portions and compressed to maketwo different shaped tablets or drug compositions. For one drug tablet,7.06 g of the drug composition is compressed with a hydraulic pressusing a flat bottom tablet punch and a deep-concave, top tablet punch.The other tablet is made by compressing 7.06 g of the drug compositionusing a flat bottom and flat top tablet punch.

Next, an expandable composition is prepared by passing separatelythrough a 40 mesh screen the following ingredients: 84.7 g of sodiumcarboxymethylcellulose with a 700,000 molecular weight, 9.4 g ofhydroxypropylcellulose with a 60,000 molecular weight, 4.7 g of sodiumchloride and 1.0 g of ferric oxide. All of the above ingredients arethoroughly mixed to provide a homogeneous mass. Then, with continuousmixing, 40 ml of denatured alcohol is added slowly and the mixing iscontinued for 2 to 3 minutes. The wet granulation is passed through a 20mesh screen, dried at room temperature for 16 hours and again passedthrough a 20 mesh screen. Finally, 0.2 g of magnesium stearate is addedto the granulation and the ingredients are mixed in a rollermill for 3to 4 minutes. The expandable composition is made into a tablet bycompressing 5.2 g of the composition in a hydraulic press using a flattop and flat bottom tablet punch.

Next, a wall-forming member designed and shaped like a cup is preparedas follows. First, 76 g of cellulose acetate butyrate having a butyrylcontent of 37% and 13% acetyl content, 15 g of polyethylene glycolhaving a 400 molecular weight and 9 g of triethyl citrate are mixed intoa homogeneous mass. Then, 10.5 g of the mixture is injection molded tomake a semipermeable walled cup with one domed (concave) end and anopposite open end and with an average wall thickness of 65 mils.

The dispenser is assembled as follows. First, a 300 mil exit port isdrilled through the concave end of the semipermeable cup. The firstdescribed drug tablet is then inserted into the semipermeable cup sothat its convex top fits into the concave end of the cup. Then, thesecond described drug tablet is inserted into the cup so that it isflush against the flat end of the first inserted drug tablet. Next, theexpandable tablet is inserted so that it is flush against the seconddrug tablet. Then, a 64 g iron densifier is inserted into the cup sothat its flat end is against the expandable tablet. Finally, the wall issealed as the open end of the cup is heated, then pressed against thedensifier and cooled to room temperature.

Dispensers prepared according to this example were placed into the rumenof a fistulated cow. The dispensers were removed from the rumen atdifferent time intervals to measure the amount of lysocellin releasedper unit time. FIG. 12 illustrates the controlled and continuous releaseof lysocellin at a rate of 85 mg/day for 126 days. In the figure, thesquares denote the cumulative amount of lysocellin released (grms.) atdifferent time (days) intervals, and the number of dispensers in thestudy were seven.

EXAMPLE 2

A dispenser sized and adapted for the controlled delivery of lysocellinis made according to the procedure set forth in Example 1, with allconditions as previously described, except that this example the drugcomposition comprising the lysocellin is present as a single compositionin the dispenser. The single composition weighs 14.12 g and comprisespolyethylene oxide having a 5,000,000 molecular weight,hydroxypropylmethylcellulose having a 11,200 molecular weight, and thelysocellin ionophore.

EXAMPLE 3

A dispenser for administering two different carboxylic ionophores,monensin and lasalocid, for increasing feed efficiency in ruminants ismanufactured according to the procedure of Example 1. In this example,the dispenser comprises two ionophore compositions, with eachcomposition comprising a different ionophore. A first compositionnearest the exit port comprises monensin sodium, polyethylene oxidehaving a 5,000,000 molecular weight and hydroxypropylmethylcellulosehaving a 11,200 molecular weight. The second composition is in immediatecontact with the first composition. The second composition compriseslasalocid, polyethylene oxide having a 3,000,000 molecular weight andhydroxypropylmethylcellulose having a 22,000 molecular weight. The restof the dispenser is as described in Example 1. The use of two differentionophores delivered into the rumen operates to maintain maximum feedefficiency. The dispenser can be manufactured for administering thefirst ionophore composition for 50 to 60 days, followed by deliveringthe second composition for 50 to 60 days.

EXAMPLE 4

A dispenser for delivering an ionophore to livestock is made byfollowing the above examples. The dispenser of this example is 75 mmlong and 25 mm in diameter. The dispenser comprises a pair ofcompositions in contacting arrangement, with each composition consistingof lasalocid, lysocelline, septamycin, nigericin, dianemycin, monensinand salinomycin; 1,054 mg of polyethylene oxide possessing a 5,000,000molecular weight; 162.50 mg of hydroxypropylmethylcellulose possessing a11,200 molecular weight; and 125 mg of magnesium stearate. The dispensercomprises a single expandable composition layer in contact with a pairof ionophore compositions. The expandable composition comprises 4,405 mgof sodium carboxymethylcellulose having a 700,000 molecular weight, 490mg of hydroxypropylcellulose, 245 mg of sodium chloride, 50 mg of ferricoxide, and 15 mg of magnesium stearate. The device contains a 64,000 mgiron densifier, a 10,500 mg cellulosic rate-controlling wall, and a 400mil diameter exit orifice or passageway.

EXAMPLE 5

A dispensing device for the controlled delivery of an ionophore into thedigestive tract of an animal is manufactured as follows. First, 57 g ofcellulose acetate having an acetyl content of 39.8% and 1.3 kg ofcellulose acetate butyrate having an acetyl content of 13% and a butyrylcontent of 37% are sized and then combined with 2.2 g of Citroflex®-2triethyl citrate and 0.3 kg of polyethylene glycol 400 in the bowl of alarge Hobart® mixer. After mixing for 20 minutes, the blended materialis transferred to the feed hopper of a Van Dorn injection molder, whichis equipped with a suitable mold to produce a 7.5 g cellulose cup havingthe approximate dimensions 6.3 cm in height×2.1 cm in width and a wallthickness of 0.13 cm.

Next, 4.0 g of a hydrophilic expandable member comprising a 70:30 ratioof sodium carboxymethylcellulose to sodium chloride, lubricated with 1%magnesium stearate, is compressed using 10,000 lbs. of force in aCarver® laboratory press equipped with a tablet tool and is theninserted into the cup.

Next, an ionophore composition comprising 10 g of an ionophore selectedfrom the group consisting of lonomycin, lentotemycin, etheromycin,isolasalocid, laidlomycin sodium salt, semduramicin, and alborixinpotassium salt; 2.1 g of poly(ethylene oxide) having a 3,500,000molecular weight; 0.325 g of hydroxypropylmethylcellulose having a11,200 molecular weight; and 0.5 g of magnesium stearate is pressed intoa solid tablet and is inserted into the cup against the expandablemember.

Then, an iron density element comprising four 50 mm exit passageways,which possesses the dual function of aiding in the retention of thedispenser in the rumen of an animal and serving as a flow moderatorthrough its multiplicity of passageways, is inserted into the open endof the dispenser and seated against the ionophore composition. Theprotruding lip of the cup is heated until softened using a hot air guncapable of delivering 600° F. air, and the lip is crimped over theperimeter of the density element to provide the dispenser.

EXAMPLE 6

A dispensing device for the delivery of lysocellin to livestock is madefollowing the procedures of the above examples. First, a semipermeablemembrane cup having a composition of 79 wt % cellulose acetate butyrate(acetyl content 13% and butyryl content 37%), 15 wt % Citroflex-2triethyl citrate and 6 wt % poly(ethylene glycol) 400 isinjection-molded into a shape having a flattened lead end and anopposite open end. Nine exit passageways (orifice channels) of 60 mildiameter each are molded into the lead end. The cup has dimensions ofapproximately 8.9 cm length, 2.5 cm width and 0.35 cm wall thickness,with the length (depth) of the passageways being 70 mil.

An ionophore composition comprising 82.0 wt % lysocellin, 16.0 wt %polyethylene oxide, 1.0 wt % hydroxypropylmethylcellulose E-5 and 1.0 wt% magnesium stearate is pressed into three solid tablets, each weighing5.0 g. One tablet is inserted into the open end of the cup and seatedagainst the lead end, the second tablet is then inserted behind thefirst, and the third tablet is inserted behind the second.

Next, 9.1 g of a hydrophilic expandable tablet is formed, the tablethaving the following composition: 63.0 wt % sodiumcarboxymethylcellulose, 30.0 wt % sodium chloride, 4.75 wt %hydroxypropylcellulose EF, 1.0 wt % hydroxypropylmethylcellulose E-5,1.0 wt % ferric oxide, and 0.25 wt % magnesium stearate. The expandabletablet is inserted into the semipermeable membrane cup behind the thirdionophore tablet.

A density element having a density of 6.7 g/cc is then placed in themembrane cup behind the expandable tablet. The protruding lip of the cupis heated until softened and the lip is crimped over the perimeter ofthe density element to provide the dispenser.

EXAMPLE 7

Lysocellin dispensers identical to those prepared in Example 6 are made,except that the lead end is of a domed rather than a flattened shape.

Dispensers were tested in vitro and also in vivo in fistulated cattle.The average release rate was 70-80 mg of lysocelline per day at week 18.Lysocellin was released from the devices for at least one to 150 days.

EXAMPLE 8

Lysocellin dispensers identical to those prepared in Example 6 are made,except that the semipermeable membrane cup is molded so that is haseither a) nine exit passageways of 75 mil diameter and 70 mil lengtheach, b) nine exit passageways of 85 mil diameter and 70 mil lengtheach, or c) nine exit passageways of 100 mil diameter and 140 mil lengtheach at its lead end.

EXAMPLE 9

A dispensing device for the delivery of tetronasin to livestock is madefollowing the procedures of the above examples. First, a semipermeablemembrane cup having a composition according to Example 6 is molded intoa shape having a flattened lead end and an opposite open end. Nine exitpassageways of 60 mil diameter each are molded into the lead end.

An ionophore composition comprising 50.0 wt % tetronasin, 21.6 wt %polyethylene oxide coagulent, 26.4 wt % barium sulfate, 1.0 wt %hydroxypropylmethylcellulose E-5 and 1.0 wt % magnesium stearate ispressed into three solid tablets, each weighing 5.0 g. One tablet isinserted into the open end of the cup and seated against the lead end,the second tablet is then inserted behind the first and the third tabletis inserted behind the second.

Next, 9.1 g of a hydrophilic expandable tablet is formed, having thesame composition as that in Example 6. The expandable tablet is insertedinto the semipermeable membrane cup behind the third ionophore tablet.

A density element having a density of 6.7 g/cc is then placed in themembrane cup behind the expandable tablet. The protruding lip of the cupis heated until softened and the lip is crimped over the perimeter ofthe density element to provide the dispenser.

EXAMPLE 10

Tetronasin dispensers identical to those prepared in Example 9 are made,except that the lead end is of a domed rather than a flattened shape.

Dispensers were tested in vitro and also in vivo in fistulated cattle.The average release rate was 55-60 mg of tetronasin per day at week 18.Tetronasin was released from the devices for at least up to 150 days.

EXAMPLE 11

Tetronasin dispensers identical to those prepared in Example 9 are made,except that the semipermeable membrane cup is molded so that it haseither a) nine exit passageways of 75 mil diameter and 70 mil lengtheach, b) nine exit passageways of 85 mil diameter and 70 mil lengtheach, or c) nine exit passageways of 100 mil diameter and 140 mil lengtheach at is lead end.

METHOD OF USING THE INVENTION

An embodiment of the invention pertains to a method for administering abeneficial ionophore at a controlled rate to the rumen of a ruminant. Incarrying out the method, a dispenser is placed into a balling gunprovided with an ejecting means, the gun is inserted into the mouth ofthe animal beyond the base of the tongue, and the dispenser is gentlyejected by applying pressure to an ejection plunger in the gun, therebysending the dispenser into the rumen. More specifically the methodcomprises the steps of: (A) admitting into an animal's rumen a dispensercomprising: (1) a wall comprising in at least a part a semipermeablepolymer composition permeable to the passage of fluid and substantiallyimpermeable to the passage of an ionophore, the wall surrounding (2) aninternal lumen or compartment, (3) a layer comprising a beneficialionophore and a pharmaceutically acceptable carrier for the ionophore inthe lumen, (4) a layer of an expandable hydrophilic polymericcomposition in the lumen, (5) a dense member in the lumen formaintaining the dispenser in the rumen over a prolonged period of time,and (6) at least one exit passageway in the wall that communicates withthe composition comprising the ionophore and the carrier; (B) imbibingfluid through the semipermeable wall at a rate determined by thepermeability of the wall and the osmotic pressure gradient across thewall, which fluid contacts the composition comprising the ionophore toform a dispensable composition and contacts the expandable compositionto cause the expandable composition to expand and push against theionophore composition; and (C) delivering the beneficial ionophorecomposition from the lumen by the expandable composition continuallyexpanding against the ionophore composition and causing the ionophore tobe dispensed in a beneficially effective amount through the exitpassageway at a controlled rate to the rumen over a prolonged period oftime.

Inasmuch as the foregoing specification comprises presently preferredembodiments of the invention, it is to be understood that variousimprovements and modifications may be made her in accordance with theinventive principles disclosed, without departing from the scope of theinvention.

What is claimed is:
 1. A dispenser for delivering a beneficial ionophoreto a fluid environment of use, the dispenser comprising:(a) a wallcomprising in at least a part a semipermeable composition permeable tothe passage of fluid and substantially impermeable to the passage of anionophore, which wall surrounds (b) a compartment; (c) a composition inthe compartment comprising an ionophore and a pharmaceuticallyacceptable carrier for the ionophore; (d) a hydrophilic polymericcomposition in the compartment that expands in the presence of fluid forpushing the composition comprising the ionophore from the dispenser; (e)a densifier in the compartment, the densifier having a specific gravitygreater than the specific gravity of fluid present in the environment ofuse; and (f) an exit passageway or multiplicity of exit passageways inthe wall for delivering a therapeutically effective amount of theionophore from the dispenser over a period of time, the diameter of eachexit passageway being of a size to maximize release of the ionophore byosmotic pumping and minimum the release of the ionophore by diffusion toavoid mechanical agitation-dependent ionophore release.
 2. A dispenseraccording to claim 1 wherein the ionophore is lysocellin.
 3. A dispenseraccording to claim 1 wherein the ionophore is tetronasin.
 4. A dispenseraccording to claim 1 wherein the ionophore is a member selected from thegroup consisting of lonomycin, lenotemycin, erythromycin, isolasalocid,laidlomycin, laidlomycin propionate, laidlomycin butyrate, semduramicin,alborixin, lasalocid, septamycin, nigericin, dianemycin, monensin, andsalinomycin, and pharmaceutically acceptable salts and esters thereof.5. A dispenser according to claim 1 wherein the dispenser delivers theionophore for about 150 days.
 6. A dispenser for delivering a beneficialionophore to a fluid environment of use, the dispenser comprising:(a) awall comprising in at least a part a nontoxic composition permeable tothe passage of fluid and substantially impermeable to the passage of anionophore, the wall surrounding and forming (b) a compartment; (c) acomposition in the compartment comprising an ionophore and apharmaceutically acceptable carrier for the ionophore; (d) a secondcomposition in the compartment comprising an ionophore and apharmaceutically acceptable carrier for the ionophore; (e) a hydrophilicpolymeric composition in the compartment comprising an osmoticcomposition that expands when contacted by fluid to displace the firstand second compositions from the dispenser; (f) a densifier in thecompartment, the densifier having a specific gravity greater than thespecific gravity of fluid present in the environment of use; and (g) anexit passageway or multiplicity of exit passageways in the wall fordelivering the first and second compositions from the dispenser intherapeutically effective amounts over a period of time, the diameter ofeach exit passageway being of a size to maximize release of theionophore by osmotic pumping and minimum the release of the ionophore bydiffusion to avoid mechanical agitation-dependent ionophore release. 7.A dispenser according to claim 6 wherein the ionophore in the firstcomposition is lysocellin or tetronasin.
 8. A dispenser according toclaim 6 wherein the ionophore in the second composition is lysocellin ortetronasin.
 9. A dispenser according to claim 6 wherein the firstcomposition and the second composition comprise the same ionophore. 10.A dispenser according to claim 9 wherein the ionophore is lysocellin ortetronasin.
 11. A dispenser according to claim 6 wherein the firstcomposition and the second composition comprise different ionophores.12. A dispenser according to claim 6 wherein the dispenser delivers anionophore for about 150 days.
 13. A dispenser according to claim 6wherein the ionophore in the first composition comprises an ionophoreselected from the group consisting of valinomycin, enniactin, monactin,nonactin, dinactin, trinactin, virginiamycin, tetronasin, semduramicin,monensin, monensin sodium, nigericin, narasin, salinomycin,isolasalocid, lasalocid, lysocellin, septamycin, laidlomycin,laidlomycin propionate, laidlomycin butyrate, lonomycin, lenotemycin,grisorixin, alborixin, erythromycin, azolomycin, and sodium lysocellin,and pharmaceutically acceptable salts and esters thereof.
 14. Adispenser according to claim 6 wherein the ionophore in the secondcomposition comprises a member selected from the group consisting ofvalinomycin, enniactin, monactin, nonactin, dinactin, trinactin,virginiamycin, tetronasin, semduramicin, monensin, monensin sodium,nigericin, narasin, salinomycin, isolasalocid, lasalocid, lysocellin,septamycin, laidlomycin, laidlomycin propionate, laidlomycin butyrate,lonomycin, lenotemycin, grisorixin, alborixin, erythromycin, azolomycin,and sodium lysocellin, and pharmaceutically acceptable salts and estersthereof.
 15. A dispenser according to claim 6 which further comprises athird composition in the compartment comprising an ionophore and apharmaceutically acceptable carrier for the ionophore.
 16. A dispenseraccording to claim 15 wherein the ionophore in the third compositioncomprises a member selected from the group consisting of valinomycin,enniactin, monactin, nonactin, dinactin, trinactin, virginiamycin,tetronasin, semduramicin, monensin, monensin sodium, nigericin, narasin,salinomycin, isolasalocid, lasalocid, lysocellin, septamycin,laidlomycin, laidlomycin propionate, laidlomycin butyrate, lonomycin,lenotemycin, grisorixin, alborixin, erythromycin, azolomycin, and sodiumlysocellin, and pharmaceutically acceptable salts and esters thereof.17. A composition for dispensing an ionophore from a drug deliverydispenser to livestock over a prolonged period of time, said compositioncomprising 10 mg to 100 g of an ionophore selected from the groupconsisting of valinomycin, enniactin, monactin, nonactin, dinactin,trinactin, virginiamycin, tetronasin, semduramicin, monensin, monensinsodium, nigericin, narasin, salinomycin, isolasalocid, lasalocid,lysocellin, septamycin, laidlomycin, laidlomycin propionate, laidlomycinbutyrate, lonomycin, lenotemycin, grisorixin, alborixin, erythromycin,azolomycin, and sodium lysocellin, and pharmaceutically acceptable saltsand esters thereof; and a pharmaceutically acceptable poly(ethyleneoxide) carrier comprising a 200,000 to 7,500,000 molecular weight.
 18. Acomposition according to claim 17 wherein the ionophore is lysocellin,laidlomycin propionate or tetronasin.
 19. A method for administering toan animal a biologically active ionophore, said method comprising:(A)admitting orally into the animal a dispenser comprising:(1) a wall thatsurrounds and forms an internal compartment, the wall comprising in atleast a part a composition permeable to the passage of fluid andsubstantially impermeable to the passage of an ionophore; (2) acomposition in the compartment comprising a biologically activeionophore selected from the group consisting of valinomycin, enniactin,monactin, nonactin, dinactin, trinactin, virginiamycin, tetronasin,semduramicin, monensin, monensin sodium, nigericin, narasin,salinomycin, isolasalocid, lasalocid, lysocellin, septamycin,laidlomycin, laidlomycin propionate, laidlomycin butyrate, lonomycin,lenotemycin, grisorixin, alborixin, erythromycin, azolomycin, and sodiumlysocellin, and pharmaceutically acceptable salts and esters thereof;and a pharmaceutically acceptable carrier for the ionophore, saidcarrier comprising a poly(ethylene oxide) comprising up to 90 wt % ofthe ionophore; (3) a hydrophilic composition in the compartment thatexpands when contacted by fluid, thereby experting pressure against theionophore composition for displacement of the ionophore composition fromthe compartment; (4) a densifier in the compartment for maintaining thedispenser in the animal over time, the densifier having a densitygreater than the density of the fluid present in the animal; and (5) anexit passageway or multiplicity of exit passageways in the wall fordelivering the biologically active ionophore from the dispenser, thediameter of each exit passageway being of a size to maximize release ofthe ionophore by osmotic pumping and minimum the release of theionophore by diffusion to avoid mechanical agitation-dependent ionophorerelease; and (B) administering the biologically active ionophore by theionophore composition absorbing fluid to form a dispensable compositionand by the hydrophilic composition absorbing fluid, expanding anddisplacing the ionophore composition through the passageway orpassageways in a therapeutically effective amount to the animal at acontrolled rate over time.
 20. A method according to claim 19 whereinthe ionophore is lysocellin, laidlomycin propionate or tetronasin.
 21. Adispenser according to claim 4 wherein the ionophore is laidlomycinpropionate.
 22. A dispenser according to claim 9 wherein the ionophoreis laidlomycin propionate.